Selective cranial multineuritis in severe COVID-19 pneumonia: two cases and literature review.

OBJECTIVE: To report two cases of cranial multineuritis after severe acute respiratory syndrome caused by coronavirus-2. METHODS: Patients' data were obtained from medical records of the clinical chart of dell'Angelo Hospital, Venice, Italy. RESULTS: The first patient is a 42-year-old male patient who developed, 10 days after the resolution of coronavirus-2 pneumonia and intensive care unit hospitalization with hyperactive delirium, a cranial multineuritis with asymmetric distribution (bilateral hypoglossus involvement and right Claude Bernard Horner syndrome). No albumin-cytologic dissociation was found in cerebrospinal fluid; severe bilateral denervation was detected in hypoglossus nerve, with normal EMG of other cranial muscles, blink reflex, and cerebral magnetic resonance with gadolinium. He presented a striking improvement after intravenous human immunoglobulin therapy. The second case is a 67-year-old male patient who developed a cranial neuritis (left hypoglossus paresis), with dyslalia and deglutition difficulties. He had cerebrospinal fluid abnormalities (albumin-cytologic dissociation), no involvement of ninth and 10th cranial nerves, diffuse hyporeflexia, and brachial diparesis. DISCUSSION: Cranial neuritis is a possible neurological manifestation of coronavirus-2 pneumonia. Etiology is not clear: it is possible a direct injury of the nervous structures by the virus through olfactory nasopharyngeal terminations. However, the presence of albumin-cytological dissociation in one patient, the sparing of the sense of smell, and the response to human immunoglobulin therapy suggests an immune-mediated genesis of the disorder.

Tacrolimus Therapeutic Drug Monitoring in Stable Kidney Transplantation and Individuation of CYP3A5 Genotype.

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.

Meltdose Tacrolimus Pharmacokinetics.

BACKGROUND: Nonadherence to immunosuppressive therapy contributes to the loss of grafts. One of the problem is the fractioning of immunosuppressive dose. In fact, it was demonstrated that a single daily dose (QD) is associated with an increased adherence to therapy compared with twice daily dosing (BID). Tacrolimus (TAC), calcineurin inhibitor, is one of immunosuppression pillar in organ transplantation and its action is strongly correlated with blood concentration and therefore the therapeutic drug monitoring is recommended in the guidelines. However, one of the critical points of TAC is the poor and variable bioavailability that influences immunosuppression, and is also responsible for adverse effects. METHODS: MeltDose® Technology is a new technology to improve efficacy and/or reduce side effects. This new technology applied to TAC (Envarsus® or LCP-TAC) has achieved 4 main objectives: (1) improved bioavailability, (2) reduced dose fractioning to one tablet per day, (3) limited variability concentrations of TAC, and (4) lower doses of TAC will be administered. RESULTS: We analyzed the pharmacokinetic profile, efficacy, and security of Envarsus®.

Optimizing the dose of mycophenolate mofetil for the maintenance treatment of lupus nephritis by therapeutic drug monitoring.

To evaluate the usefulness of monitoring the pharmacokinetic of mycophenolic acid (MPA) in lupus nephritis (LN), in order to optimize the mycophenolate mofetil (MMF) dose in the single patient. Five consecutive patients with active LN were studied. After standard induction therapy with MMF, MMF was titrated to achieve a stable target of MPA-AUC0-12h of 45-60 mg.h/l during the maintenance treatment. For MPA assays, blood samples were collected at 0, ½, 1 », 2, 4, 6, 8 and 12 h after the morning dose. Plasma MPA concentration was measured using a validated high-performance liquid chromatography. Treatment response was evaluated at baseline, i.e. at the end of the induction therapy and during maintenance therapy with MMF. The average whole follow-up was 21.4 months. At the last visit, a complete renal response was registered in all the five patients. No renal flares were observed. Glucocorticoids were suspended in all. The mean MPA-AUC0-12h of MMF at the last visit [56.74 (±2.9) mg.h/l] was significantly lower than MPA-AUC0-12h at baseline [98.7 (±24.6) mg.h/l] (p = 0.009), since the dose of MMF was significantly reduced in all the patients [from 2.8 g/day (±0.4) to 1.9 g/day (±0.4) (p = 0.018)] based on the target MPA-AUC. No severe adverse events were observed. Assessment of MPA pharmacokinetics may be useful to optimize the maintenance therapy of lupus nephritis with MMF, possibly improving the efficacy and minimizing the side effects.

Validation of limited sampling strategy for estimation of mycophenolic acid exposure during the first year after heart transplantation.

BACKGROUND: Individualization of mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) therapeutic drug monitoring may minimize the risk of organ transplant rejection. The MPA area under the 12-hour concentration-time curve (MPA-AUC(0-12h)) is a more powerful predictor of rejection than are MPA trough levels. Measurement of MPA-AUC(0-12h,) however, is difficult and clinically impractical. The limited sampling strategy (LLS) has been proposed to overcome this problem. OBJECTIVE: To validate the predictive performance of MPA LSS algorithms previously published for heart transplant (HTx) recipients (initial group) when applied to a new independent group of 29 HTx recipients (validation group) during the first year after transplantation. PATIENTS AND METHODS: In a previous study, we established 2 algorithms using a LSS in HTx recipients: (1) 5.568 + 0.902 x C(1.25) + 2.022 x C(2) + 4.594 x C(6) and (2) 3.8 + 1.025 . C(1.25) + 1.819 x C(2) + 1.566 x C(4) + 3.479 x C(6). Agreement between abbreviated AUC and the full AUC(0-12h) was tested using the Bland-Altman method. The validation group was used to test and assess bias and precision. RESULTS: The 2 LSS algorithms used predicted the corresponding MPA-AUC(0-12h) with a mean bias of -4.85% and -3.6% and mean precision of 15.9% and 14%, respectively. CONCLUSIONS: The MPA-AUC(0-12h) obtained using the LSS may be useful to guide clinical management and dosing. This study prospectively validates 2 algorithms for calculation of MPA-AUC(0-12h) using an LSS calculated in HTx recipients. Bias and precision values suggest that our algorithms could be used for MPA therapeutic drug monitoring predictions in HTx recipients who share the same characteristics.

Therapeutic mycophenolic acid monitoring by means of limited sampling strategy in orthotopic heart transplant patients.

Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM of mycophenolate mofetil requires area under the curve AUC determinations but appears laborious, costly, and clinically impractical. To overcome these problems, limited sampling strategies (LSS) have been proposed in adult and pediatric renal transplant patients. The purpose of this study was to develop an LSS in heart transplant patients. Forty-four mycophenolic acid (MPA) full AUC(0-12h) profiles were generated by high-performance liquid chromatography in nine heart transplant patients during the first 12 weeks posttransplant. Each patient received concomitant cyclosporine and prednisone therapy. Multiple stepwise regression analysis was used to define the time points of MPA levels to explain the MPA AUC(0-12h). Agreement between abbreviated AUC and the full AUC(0-12h) was tested by means of a Bland and Altman analysis. The highest coefficient of determination r(2) among MPA AUC and single concentrations (r(2) = .610) was observed with C(2), while C(12) provided the lowest one (r(2) = .003). Stepwise linear regression showed that the minimal model with the best estimation of MPA AUC(0-12h) was obtained at timed values of 1.25, 2, and 6 hours. The corresponding estimated model was AUC = 5.568 + 0.902 * C(1.25) + 2.022 * C(2) + 4.594 * C(6) (r(2) = .926). Bland and Altman analysis revealed good agreement between predicted AUC and full AUC. A further interesting model equation obtained by four samples was AUC = 3.800 + 1.015 * C(1.25) + 1.819 * C(2) + 1.566 * C(4) + 3.479 * C(6) (r(2) = .948).

Circadian variations in cyclosporine C2 concentrations during the first 2 weeks after liver transplantation.

The strategies currently used to monitor concentrations of cyclosporine (CsA) in transplanted patients include whole blood trough (C0), total or abbreviated area under the curve (AUC) concentration and population pharmacokinetic approaches. Recently, a single blood concentration measurement at 2 hours (C2) after CsA administration has been shown to be helpful to predict clinical effects during the first weeks after transplantation of liver and kidney grafts. However, this approach has raised multiple questions about pharmacokinetic variability, analytical methods, and organizational requirements. From a pharmacokinetic point of view, the variability of CsA blood concentrations may relate to circadian variations. The present study sought to characterize the circadian variation in C0 and C2 CsA levels among 20 liver transplant recipients during the first 2 weeks posttransplant. All patients received two equal oral doses of CsA microemulsion formulation every 12 hours. Blood samples were collected before and 2 hours after CsA administration in the morning (AM) and in the evening (PM). Whole blood concentrations of CsA were assayed using the monoclonal fluorescence polarization immunoassay system. During the first 2 weeks posttransplant, C2 AM mean levels were significantly higher than C2 PM levels (542 +/- 241 vs 383 +/- 182 ng/mL, P =.005), while the C0 AM mean level was not statistically different from the C0 PM (285 +/- 174 vs 223 +/- 124 ng/mL, P =.367). Our results suggest that morning CsA blood samples may afford a better approach to optimize the CsA dosage, especially based on C2 values.

Cerebrospinal fluid penetration of levofloxacin in patients with spontaneous acute bacterial meningitis.

We have assessed levofloxacin penetration in cerebrospinal fluid (CSF) and the liquor-to-plasma ratio (C(L)/C(P)) at 2 hours after dosing in 5 patients with spontaneous acute bacterial meningitis. CSF levofloxacin concentration at 2 hours after dosing was 1.99+/-0.67 microg/mL, and the C(L)/C(P) at 2 hours after dosing was 0.34+/-0.09.

Pharmacokinetics of two oral cyclosporin a formulations in clinically stable heart-transplant patients.

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14 +/- 0.4 mgkg(-1)body weight) of CsA-SCG. The steady-state area under the concentration-time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in C(max)(ss)( 732 +/- 178 vs 935 +/- 250 ng ml(-1), P< 0.001) and t(max)( 2.63 +/- 1.21 vs 1.36 +/- 0.49 h, P< 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG ( 75 +/- 19 vs 66 +/- 16%;P< 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations.

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia.

Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t1/2alpha 4.54 +/- 0.87 h; VdSS 2.88 +/- 0.93 l/m2; Cl 0.47 +/- 0.26 l/h/m2) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC0-infinity 456.27 +/- 182.64 microg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200-to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 +/- 7.13 microg/ml x h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorubicin captation in normal tissues. thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy.

Ciprofloxacin disposition in elderly patients with LRTI being treated with sequential therapy (200 mg intravenously twice daily followed by 500 mg per os twice daily): comparative pharmacokinetics and the role of therapeutic drug monitoring.

Ciprofloxacin is a fluoroquinolone antibiotic effective in the treatment of lower respiratory tract infections (LRTI). The aim of this study was to assess the pharmacokinetic appropriateness of a standard switch i.v./os regimen of ciprofloxacin (200 mg i.v. bid for 3 to 5 days followed by 500 mg os bid for 7 to 10 days) frequently used in routine clinical practice in the treatment of elderly patients with mild to moderate LRTI. The pharmacokinetic study was performed on a cohort of 17 elderly inpatients. Blood samples were collected in steady state conditions at appropriate intervals. Ciprofloxacin serum concentrations were analyzed using an HPLC method and pharmacokinetic parameters were estimated using the WinNonlin software package. The pharmacokinetic data were at least partially different from those obtained by other authors in elderly patients (lower Cmax after i.v. administration and higher CL both after i.v. and oral administration). Cmax after a 1-hour 200-mg infusion were similar to those observed during the 500 mg bid peroral regimen (2.1 +/- 0.9 mg/L vs 2.6 +/- 1.0 mg/L; p = 0.054). The absolute oral bioavailability (84.1%) allowed a total body exposure 2.1-fold greater after 500 mg bid oral administration than after 200 mg bid i.v. administration (AUC(0-tau) 11.4 +/- 4.3 mg/L x h vs 5.5 +/- 1.8 mg/L x h). The results show that in malabsorption-free elderly patients a regimen of 500 mg os bid may be considered a valid therapeutic approach from the beginning of therapy for mild to moderate LRTI caused by sensitive microorganisms (MIC < 0.1 mg/L). In fact, because the peak serum level to MIC ratio (Cmax/MIC) and the area under the inhibitory serum concentration-time curve (AUIC24 = AUC24h/MIC) are actually considered major pharmacodynamic determinants for the outcome of treatment with fluoroquinolones, this regimen could guarantee both a better pharmacokinetic exposure than the 200 mg i.v. bid regimen and a cost-effective treatment of LRTI. However, because of the great pharmacokinetic interindividual variability observed a normalized dosage per kg (3 mg/kg/12h i.v. and 8 mg/kg/12h os) should be considered, especially for body weight >90 kg and, whenever possible, TDM of AUC(0-tau) or at least of Cmax should be performed to individualize therapy in this subpopulation.

High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures.

The aim of this study was to evaluate retrospectively the importance of a Bayesian pharmacokinetic approach for predicting vancomycin concentrations to individualize its dosing regimen in 18 critically ill patients admitted to intensive care units following cardiothoracic surgery. The possible influence of some coadministered drugs with important haemodynamic effects (dopamine, dobutamine, frusemide) on vancomycin pharmacokinetics was assessed. Vancomycin serum concentrations were measured by fluorescence polarization immunoassay. Vancomycin dosage regimens predicted by the Bayesian method (D(a)) were compared retrospectively with Moellering's nomogram-based dosages (D(M)) to assess possible major differences in vancomycin dosing. D(a) values were similar to D(M) in 10 patients (D(a) approximately D(M) group) (20.52 +/- 8.40 mg/kg/day versus 18.81 +/- 7.24 mg/kg; P = 0.15), whereas much higher dosages were required in the other eight patients (D(a) >> D(M) group) (26.78 +/- 3.01 mg/kg/day versus 18.95 +/- 3.41 mg/kg/day; P < 0.0001) despite no major difference in attained vancomycin steady-state trough concentration (C(min ss)) (9.22 +/- 1. 33 mg/L versus 8.99 +/- 1.26 mg/L; = 0.75) or estimated creatinine clearance (1.23 +/- 0.49 mL/min/kg versus 1.21 +/- 0.24 mL/min/kg; P = 0.95) being found between the two groups. The ratio between D(a) and D(M) was significantly higher in the D(a) >> D(M) group than in the D(a) approximately D(M) group (1.44 +/- 0.18 versus 1.10 +/- 0. 21; P < 0.01). In four D(a) >> D(M) patients the withdrawal of cotreatment with haemodynamically active drugs was followed by a sudden substantial increase in the vancomycin C(min ss) (13.30 +/- 1. 13 mg/L versus 8.79 +/- 0.87 mg/L; P < 0.01), despite no major change in bodyweight or estimated creatinine clearance being observed. We postulate that these drugs with important haemodynamic effects may enhance vancomycin clearance by inducing an improvement in cardiac output and/or renal blood flow, and/or by interacting with the renal anion transport system, and thus by causing an increased glomerular filtration rate and renal tubular secretion. Given the wide simultaneous use of vancomycin and dopamine and/or dobutamine and/or frusemide in patients admitted to intensive care units, clinicians must be aware of possible subtherapeutic serum vancomycin concentrations when these drugs are coadministered. Therefore, therapeutic drug monitoring (TDM) for the pharmacokinetic optimization of vancomycin therapy is strongly recommended in these situations.

Inter-patient and intra-patient variations in the baseline tapping test in patients with Parkinson's disease.

Inter-patient and intra-patient variations in the baseline values of the tapping test were studied in 22 patients with Parkinson's disease using the unequal sample sizes model II one-way analysis of variance (ANOVA). The results show that intra-patient variation accounts for about 15.8% of the total variation, inter-patient variation accounts for about 84.2% of the total variation, and the coefficient of variation (CV) in intra-patient variation is 15.8%. The results suggest that at least two or three baseline tapping tests are needed to determine the baseline value of the tapping test.

Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia.

OBJECTIVE: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. METHODS: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. RESULTS: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); P < 0.01] and IDAOL [2896.60 (736.38) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l x h(-1) x m(-2) vs 139.65 (69.45) l x h(-1) x m(-2); NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) microg x h x l(-1) vs 2896.60 (736.38) microg x h x l(-1); P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. CONCLUSION: The results show that CyA alone at a dose of 10 mg x kg(-1) daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered.

Cyclosporine A pharmacokinetics in rheumatoid arthritis patients after 6 months of methotrexate therapy.

To evaluate the effects of a 6-month methotrexate (MTX) treatment period on cyclosporine A (CsA) pharmacokinetics were subsequently added in patients with rheumatoid arthritis (RA) in comparison with patients treated with CsA only, CsA was administered to 30 subjects with RA (group A) treated with MTX (10 mg week-1 i.m.) for 6 months and to 30 patients (group B) who received no MTX treatment. The mean doses +/- SD of CsA used in groups A and B were 3.2 +/- 0.5 and 3.3 +/- 0.4 mg kg-1, respectively. CsA levels were determined in whole blood by means of a fluorescence polarization immunoassay (FPIA) method with a specific monoclonal antibody. The following pharmacokinetics parameters were calculated: area under the curve from 0 to 24 h (AUC0-24), half-life of the elimination phase (T1/2 beta), total body clearance CL.F-1; V.F-1 and apparent volume of distribution (Vd beta). The mean blood concentrations and the pharmacokinetic parameters calculated in group A did not present significant statistical differences in comparison to group B. In conclusion, a 6-month MTX therapy does not produce liver function modifications to such an extent as to modify the pharmacokinetics of CsA subsequently added. Therefore, from a clinical pharmacological point of view, an MTX-CsA cotreatment appears feasible.

Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in acute non-lymphocytic leukemia.

P-glycoprotein (Pgp)-related multidrug resistance (MDR) is frequently observed in acute non-lymphocytic leukemia (ANLL) and is associated with a poor response to standard chemotherapy. Cyclosporin A (CsA) is an effective downmodulator of Pgp-related MDR in vitro and has already been tested for that purpose in vivo also. Since Pgp is expressed in several normal cells and tissues, the modulation of Pgp can also modify total body exposure to antileukemic drugs and can alter and increase the toxicity of the antileukemic treatment. We report here the results of a study where 46 consecutive adult patients with ANLL were assigned to receive the same standard chemotherapy regimen of arabinosyl cytosine and idarubicin (IDA) for remission induction or consolidation, without or with CsA. Twenty-eight patients received 36 courses of chemotherapy without CsA and 18 patients received 32 courses of chemotherapy with CsA. CsA dose was 10-12.5 mg/kg/day and was given as a continuous i.v. infusion for 72 h. Whole blood CsA steady-state concentration ranged between 0.61 and 1.14 microM. The IDA area-under-the-curve was about twice as high in the cases that received CsA than in the other cases. CsA had no detectable effects on renal function and fluid balance, but significantly increased systemic blood diastolic pressure and conjugated bilirubine concentration. Furthermore, CsA-treated patients had greater, and more severe, oral and intestinal mucosal toxicity, with more severe adverse events, including more cases of gram-negative bacteremia, and with a delayed hemopoietic recovery. In conclusion, this study showed that an attempt at an effective downmodulation of Pgp-mediated MDR would substantially increase the hemopoietic and mucosal toxicity of antileukemic treatment and that the increase is accounted for, at least in part, by an increase of total body exposure to IDA.

Levodopa and 3-O-methyldopa in cerebrospinal fluid after levodopa-carbidopa association.

Since motor fluctuations in Parkinsonian patients might be, at least in part, explained by an antagonism between levodopa (LD) and its metabolite 3-O-methyldopa (3-OMD) at blood-brain-barrier (BBB), we decided to study LD and 3-OMD plasma and cerebrospinal fluid (CSF) levels in subjects undergoing lumbar puncture for diagnostic purposes. After informed consent, 70 subjects took a tablet of carbidopa-levodopa association (Sinemet or Sinemet-CR) 0.5, 1, 2, 4, 8, 12 h before blood and lumbar cerebrospinal fluid collection. LD and 3-OMD were determined by an HPLC-electrochemical method. The subjects treated with Sinemet-CR had lower LD cerebrospinal fluid concentrations along with lower LD and higher 3-OMD plasma concentrations. This pattern of LD cerebrospinal fluid concentrations may be explained by means of a transport competition between LD and 3-OMD at blood brain barrier level.